1. Field of the Invention
The present invention relates to diagnostic imaging contrast compositions and method of using such compositions. More particularly, the present invention relates to imaging blood clots or plaque disposed within a body lumen, especially those of the circulatory system, and provide extended visualization for invasive medical diagnostic and therapeutic procedures.
2. Description of the Prior Art
Contrast materials have long been used in a variety of medical imaging procedures to enhance the contrast of patient images. Contrast materials or media containing contrast materials may, for example, be employed with x-ray, magnetic resonance and ultrasound imaging. Such imaging procedures involve visualization of lumens, such as blood vessels in cardiac angiography, either by x-ray imaging or by magnetic resonance imaging (MRI), intravenous urography or kidney imaging, computerized tomography, neurological visualization of the central nervous system (i.e., the spinal cord, brain etc.), the digestive tract, lymphatics, bronchi, biliary ducts and the like. Imaging procedures are widely used in the practice of contemporary medicine. There are more than 10 million x-ray radiological examinations involving the use of contrast media performed each year in the United States and the number is growing. It is estimated that approximately 5-10% of these procedures are accompanied by clinical side effects with life threatening complications occurring in a portion of such procedures. The use of any particular contrast medium is related to its diagnostic efficacy, its toxicity, its ease of storage and administration, and by consideration of adverse effects it may have on the patient to which it is administered. It is desirable to have contrast media that are effective and have as few as possible deleterious physiological effects on body cells or organs.
In medical procedures involving the use of contrast media, there are several undesirable side effects including hyperosmotic damage, iodine-specific toxicity, kidney damage, and radiation damage. As an example, it is typical to inject 100-200 mL of contrast medium into a total plasma volume of 5 liters within a period of several minutes. Cells, such as endothelial cells, red blood cells, white blood cells, kidney cell etc., are exposed to a hyperosmotic solution in comparison to the osmolarity of the blood. This gives rise to hyperosmotic shock which may produce damage. This hypertonicity causes osmotic effects, such as the draining of water from red blood cells, endothelia cells, and heart and blood vessel muscle cells. Hypertonicity, chemotoxicity, and non-optimal ionic composition either individually or collectively reduce the contractile force of the muscle cells and cause dilation of small blood vessels and result in a decrease in blood pressure.
Iodine is commonly used in contrast media. For example, in an x-ray visualization procedure typically 30-40 grams of iodine/contrast medium are injected into the blood within a period of about 2-10 minutes. Visualization of a target requires a minimum accumulation of 15-20 mg of iodine/ml in the target tissue. For this reason, the initial iodine concentration of the contrast medium is relatively high (i.e., in the range of about 300 to 420 mg iodine/ml of medium). Iodinated aromatic compounds may be used as x-ray contrast materials. U.S. Pat. No. 6,406,680 is directed to iodinated alkenes for use as x-ray contrast materials reported as equivalent to iodinated aromatic contrast materials. Compounds that can release iodide in reactions with nucleophiles or electrophiles may cause toxic biological effects and preferably should not be used as contrast materials.
As iodine is a common contrast material, the iodine load to which the kidney is exposed and needs to excrete is a potential cause for renal damage. In general, it is believed that about 12% of all patients that are injected with an x-ray contrast medium encounter renal complications. In cardiac catheterization, for example, from 9-16% of patients develop renal failure depending upon whether they are high or low risk patients. It is well known that exposure of cells to x-ray contrast medium causes cell damage. In addition, with commercial x-ray contrast media having high concentrations of iodine of about 300 mg iodine/mL, these media have a relatively high viscosity at ambient temperature. Such high viscosity is troublesome to the provider of the contrast medium and requires relatively large bore needles or high-applied pressure. This is particularly significant in pediatric radiography and in radiographic techniques, such as angiography, which require rapid bolus administration. Although the toxicity of iodine as a contrast material is notable, toxicity and adverse biological effects of a contrast medium are attributed to the components of a the medium, such as the solvent or carrier, as well as the contrast material itself and its components (i.e., ions if ionic) and various metabolites.
Coronary angiography is an important procedure in the diagnosis of medical problems associated with the coronary arteries that supply blood to the heart. During this procedure, the coronary arteries are imaged so as to enable the medical practitioner to observe any blood circulation problems that may affect the heart. A radio-opaque contrast substance (i.e., contrast medium with iodine as the active contrast material) injected into the coronary arteries during the angiography procedure causes the arteries to appear as bright lines contrasted against a relatively darker background. Where a stenosis or restriction is present in a coronary artery, the artery will appear to be pinched and will have a smaller cross-sectional thickness at the location of the restriction. It is typically necessary to produce at least five angiography sequences at different projection angles relative to the heart to obtain visual images of all portions of the coronary arterial system for accurate medical diagnosis.
During angiography, a radio-opaque contrast substance is injected into one of the coronary arteries and consecutive frames (i.e., from about 150 to 250) are recorded on film with a cine camera, video camera, and/or recorded in digital format. Multiple injections or sequences are usually involved with an angiography procedure. Each sequence records from 5 to 15 heartbeats or cardiac cycles. During each beat of the heart, ventricles fill with blood during diastole and reach their maximum volume at the end of diastole. The heart muscle then contracts during the systole phase, and the ventricles reach their minimum volume of blood at the end of systole. The filling of the coronary arteries with blood takes place primarily during diastole as the coronary arteries pass through the heart muscle and the pressure exerted by the contracting muscle during the systole phase tends to impede blood flow through the arteries. During the imaging procedure, the injected radio-opaque contrast substance can be seen to fill the coronary artery and then to gradually clear from the artery as fresh blood devoid of the contrast substance enters the artery.
Contrast media used in coronary angiography are injected into the circulatory system and have been associated with several serious adverse effects on cardiac function. In this procedure following injection of the contrast medium, a bolus of the contrast medium rather than blood flows through the circulatory system. Differences in the chemical and physical nature of the contrast medium and the blood that it displaces temporarily may produce undesirable side effects, such as arrhythmias, reduction in cardiac contractile force, ventricular fibrillation and the like. Accordingly, it is a desirable objective to reduce such negative effects on cardiac function from the infusion of contrast media into the circulatory system during angiography and other similar procedures. In MRI methodology for visualization of blood vessels, a paramagnetic substance dissolved in a hyperosmotic contrast medium is injected. Factors contributing to contrast media toxicity are chemotoxicity of the contrast material, osmolalilty of the contrast medium, and the ionic/non-ionic composition of the contrast medium.
Coronary artery disease is currently the leading cause of death in the Western Hemisphere. Accordingly, visualization of the coronary arteries is a critical step in the diagnosis, treatment and prevention of death and disability from this disease. While angiography, the mapping of blood vessels, is performed with a number of techniques, the most commonly employed procedures involve invasive techniques (i.e., x-ray angiography, nuclear medicine, or surgery). Angiography commonly involves the injection for contrast of an x-ray opaque dye into the patient, allowing a period of time to pass in order to permit the dye to become circulated within the blood stream, and thereafter exposing the patient to ionizing radiation (e.g., x-rays) in order to image the patient's blood vessels. In x-ray radiography, a catheter for injection of contrast material is inserted into the artery through the groin area of a patient. Passive non-invasive techniques such as magnetic resonance imaging may also be employed. U.S. Pat. No. 6,265,875 is directed to a method of MRI tissue differentiation.
The various visualization techniques each have their disadvantages. For example, x-ray techniques expose both the patient and provider to dangerous ionizing radiation in order to image blood vessels of the patient. While in general exposure to x-rays (i.e., ionizing radiation) is preferably avoided, it is particularly undesirable in certain circumstances (i.e., pregnancy). Angiography generally requires high contrast between tissue and blood vessels in a patient to visualize blood vessels. In MRI systems, the patient must remain still for an extended period of time and expensive equipment is required. There is need for a methodology which allows angiography and other lumen visualizations without some of the disadvantages of conventional systems.
Other adverse side effects are associated with the use of contrast media. For example, patients often experience discomfort. Such discomfort is very commonly in the form of a burning sensation, experienced when the contrast medium is injected and subsequent to the injection. The severity and duration of such discomfort increases as the amount of contrast medium injected is increased. Also, contrast media may adversely affect a patient's kidneys. The extent of the effect of the contrast media on the patient's kidneys will depend on the patient's renal health and the amount and type of contrast media used. Contrast media generally fall into two general categories: (i) ionic contrast media; and (ii) non-ionic contrast media. In these groups, the contrast material in a carrier fluid is either in ionic form or in molecular or particulate form. In general, it is advisable to minimize the amount of contrast media employed. The amount of contrast medium used should be the smallest or minimal amount needed to provide diagnostically useful images of targets.
U.S. Pat. No. 5,394,874 is directed to angiography using ultrasound. Pulse echo ultrasonic imaging technology is used for examining the internal structure and functioning of living organisms, including blood flow. In medical diagnoses of various conditions, it is useful to examine soft tissues and/or blood flow to show structural details of body organs and vessels in the organs. In the examination of internal body structures, ultrasonic images are formed by producing very short pulses of ultrasound using a transducer, sending the pulses through the body, and thereafter measuring the properties of the echoes (e.g., amplitude and phase) from targets at various depths within the body. Typically, the ultrasound beam is focused at various depths within the body in order to improve resolution or image quality. A transducer receives the echoes, typically the same transducer used for transmission, and processed to generate an image of the target. Measuring and imaging blood flow, or other fluid flow, in the human body is typically done using the well-established Doppler principle, where a transmitted burst of ultrasound at a specific frequency is reflected from moving blood cells, thereby changing the frequency of the reflected ultrasound in accordance with the velocity and direction of the flow.
Regardless of the radiological imaging system (i.e., magnetic resonance imaging, computed tomography, or conventional radiograpahy using x-ray) or the part of the body being imaged, contrast-enhancing compositions are quite useful and widely employed by medical professionals. The use of contrast materials as adjuncts in radiological imaging makes it possible to determine the location, size, and conformation of organs or other structures of the body relative to surrounding tissues or structures. The various imaging systems, including radiological and sound systems, operate on distinct physical principles, and each may be used to differentiate between normal tissue, tumors, lesions, blockages and the like, but all may employ contrast materials. For example, in the diagnosis of disorders of the gastrointestinal (GI) tract, it is difficult to identify blockages or abnormalities in the conformation of the intestine unless the particular section of the GI tract under investigation is filled with a contrast material which facilitates definition of volumes and delineation of boundaries.
In conventional radiography, a beam of x-rays passes through a target and exposes an underlying photographic film thereby providing a visual image. The developed film gives an image of the radiodensity pattern of the target object. Less radio-dense areas show a blackening of the film and more radio-dense area (i.e., bone) produce a lighter image. Contrast materials for use with x-ray radiography may be either less or more radiodense than body tissues. Examples of less radio-dense contrast materials include air or other gases (i.e., carbon dioxide for use in the GI tract). Examples of more radio-dense contrast material included iodine compositions, barium sulfate suspensions, clay-based compositions, and the like. U.S. Pat. No. 3,975,512 is directed to the use of fluorocarbons as contrast enhancement media in radiological imaging. Depending on the imaging requirement, contrast materials are introduced into the body in various ways (i.e., orally with the GI tract; injection with coronary angiography). Regardless of the imaging system, a suitable contrast material must be biocompatible. Contrast materials should be non-toxic, chemically stable, should not be absorbed by the body or reactive within tissue, and should be safely eliminated from the body within a short period of time.
With reference to magnetic resonance imaging (MRI), a different physical principle is employed. MRI takes advantage of the fact that some atomic nuclei (e.g., hydrogen nuclei) have both nuclear spin and nuclear magnetic moment can therefore be manipulated by applied magnetic field. In conventional MRI systems, a magnetic field is established across a body to align the spin axes of the nuclei of a particular chemical element, usually hydrogen, with the direction of the magnetic field. The aligned spinning nuclei execute motions around the aligning direction of the magnetic field. The frequency at which the aligned spinning nuclei process around the direction of the magnetic field is a function of the particular nucleus which is involved and the strength of the magnetic field. In commercial MRI systems following alignment or polarization of the selected nuclei, a burst of radio frequency energy at the resonant frequency is radiated at the target object to produce a coherent deflection of the spin alignment of the selected nuclei. When the deflecting radio energy is terminated, the deflected or disturbed spin axes are reoriented or realigned and radiate a characteristic radio frequency signal which can be detected and analyzed. The MRI system can establish image contrast between different types of tissues in the body. A wide variety of different excitation and discrimination modes are known in the art. Accordingly, contrast materials for MRI must possess a substantially different concentration of the nuclei used as a basis for scanning. In a hydrogen scanning system, an imaging agent substantially lacking hydrogen can be used. In a MRI system scanning for a physiologically minor nucleus, e.g., fluorine nuclei, an imaging substance with a high concentration of hydrogen would provide appropriate contrast.
While MRI utilizes radio frequency pulses and magnetic field gradients applied to a patient in a strong field to produce visual images, contrast materials are used to improve magnetic resonance images. Such contrast materials include magnetizable substances having metals or metallic compounds. Such contrast materials may be paramagnetic, ferromagnetic, or supermagnetic and act through dipole interactions with tissue protons. Most magnetic resonance imaging contrast materials have similar mechanisms of action. Most are based on gadolinium chelates and are paramagnetic agents that develop a magnetic moment when placed in a magnetic. Magnetic resonance contrast materials are increasingly being used for magnetic resonance angiography. Both arterial and venous signals become equally enhanced. With current contrast materials, there is difficulty eliminating either arterial or venous signals for flow discrimination. Automatic bolus detection addresses this issue when the blood flow is in the arterial phase. However, with the contrast material in place, subsequent data must contend with the increased venous signal intensity as the contrast material continues to distribute in the system. In addition, it is expected that that the use of intravascular contrast materials with much longer persistence will require more novel techniques for arterial-venous discrimination. U.S. Pat. No. 6,192,264 is directed to a method for MRI venography including arterial and venous discrimination. Phase contrast magnetic resonance angiography is used for imaging blood flow.
Following heart disease and cancer, the most common cause of death in the United States is cerebrovascular disease. The most common cerebrovascular pathologies are: (i) stenoses or narrowing due to vessel degeneration; (ii) aneurysms or bulges; and (iii) arteriovenous malformations which act as short circuits. Hemorrhage and other incidents attributable to these pathologies or acute thrombogenesis leading to vessel constriction or blockage can led to stroke resulting in death or devastating disabilities. Diagnostic imaging as well as therapeutic image-guided procedures are used in the treatment of cerebrovascular diseases.
In the past, the treatment of choice for vascular disease was invasive surgery that inherently carries substantial risks. More recently, image-guided minimally invasive endovascular treatments are becoming increasingly preferred for medical treatment. Such endovascular treatments are primarily radiographically related procedures. As new procedures are developed involving smaller and smaller catheters and devices, great importance is placed on image quality. There is a growing requirement for high spatial resolution during endovascular interventions or treatment. For example, balloon expansion of a stent or attempts to mold the stent within the treated vessel depend upon images with adequate detail. Visualizing the spatial relationship between overlapping stents, where required, is difficult. Also, detecting the movement of stents during the placement process is challenging. With newer stents having smaller gauge wire and more complex design, it is becoming very difficult to see even the gross shape of the stent, let alone to determine the status of the individual segment or wires of such devices. As endovascular devices progress toward treatment of smaller vessels (i.e., within or beyond the Circle of Willis) there will be the additional concern about disturbing or blocking the origin or perforators. These perforators are micro in size and are often extremely important vessels for specific, key neurological functions, which if blocked can produce devastating effects in the patient. Perforators seen during invasive microsurgery typically cannot be visualized easily, if at all, during conventional image-guided endovascular procedures. For aneurysm treatment with detachable coils, the thin strands of overlapping coils are typically blurred together into a dense mass with standard equipment. Visualization of the detailed shape of the aneurysm and the location and spacing of coil loops could determine the success or failure of the treatment.